Endo180 (MRC2) Antibody-Drug Conjugate for the Treatment of Sarcoma.
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Embargo End Date
ICR Authors
Authors
Evans, RJ
Perkins, DW
Selfe, J
Kelsey, A
Birch, GP
Shipley, JM
Schipper, K
Isacke, CM
Perkins, DW
Selfe, J
Kelsey, A
Birch, GP
Shipley, JM
Schipper, K
Isacke, CM
Document Type
Journal Article
Date
2023-02-01
Date Accepted
2022-11-02
Abstract
Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first-line treatment remains high, and the survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From the IHC staining of a large set of 625 human soft-tissue sarcomas, we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene-expression data sets showing a significantly increased expression in both soft-tissue and bone sarcomas compared with normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the antimitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180-expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on-target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide preclinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease.
Citation
Molecular Cancer Therapeutics, 2022, pp. MCT-22-0312 -
Source Title
Molecular Cancer Therapeutics
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1535-7163
eISSN
1538-8514
1538-8514
1538-8514
Collections
Research Team
Molecular Cell Biology
Sarcoma Mol Pathol
Sarcoma Mol Pathol